In the field of taste, our focus for the past fifteen years has been the isolation and characterization of genes encoding taste receptors and using these to mark the cells, define the corresponding signaling pathways, dissect receptor specificity, generate topographic maps, and trace the respective neuronal connectivity circuits. This research continues to involve a long standing and wide ranging collaboration with Charles Zuker and his groups at Columbia University and Janelia Farm. Our work has identified and characterized two families of G-protein coupled receptors, T1Rs and T2Rs, that are expressed in distinct subsets of taste receptor cells and that include functionally validated sweet, amino acid and bitter taste receptors. In addition, we have shown that the TRP-ion channel PKD2L1 is selectively expressed in acid sensing cells and have demonstrated that the taste of NaCl (and salt attraction in mice) is critically dependent on ENaC. We have also developed many genetically engineered mouse lines that have had a major impact in our understanding of how sweet, bitter, sour, salty and umami tastes are encoded at the periphery. Overall, molecular and molecular genetic studies coupled with behavioral and electrophysiological recordings have strongly supported a labeled line coding for most taste information. In this reporting period, we have demonstrated that high concentrations of salts (including non-sodium salts) activate the cells that express the T2R (bitter) taste receptors and the cells that express PKD2L1 and respond to acid stimuli. The activation of these 2 populations of taste receptor cells that detect aversive stimuli accounts for the behavioral rejection of highly concentrated salt and in combination with activation of ENaC by low concentrations of NaCl explains why salt is attractive at low concentrations but rapidly becomes aversive as concentration rises. We also continue to study taste coding at the periphery, in particular by exploring the cells and molecules involved in detecting taste qualities that do not have well characterized receptor mechanisms. In the field of olfaction, our focus has been on the development of methods whereby we can control the expression of odorant receptors. In mice, the odorant receptors are encoded by a family of more than a 1000 genes. A fundamental feature of the mammalian olfactory system is that each olfactory sensory neuron expresses just a single member of this vast family of genes. However, the details of the control of odorant receptor gene expression remain unexplained. In a collaborative project with Leonardo Belluscio, we have demonstrated new aspects of regulation that contribute to the control of odorant gene expression and have devised a system that can reliably generate mice expressing a single odorant receptor in the vast majority of olfactory sensory neurons. Previous studies from other groups have shown that odorant receptors play a key role in establishing a chemotopic map in the olfactory bulb by controlling the precise location where the primary sensory neuron makes synaptic connections with secondary neurons. Again the details of this process remain unknown and are one focus of our research. We are also using various approaches to manipulate odorant receptor expression to investigate the role these receptors play in establishing the connectivity of olfactory sensory neuron in the olfactory bulb and how this influences odor discrimination. In this reporting period we have continued to characterize the behavioral and physiological responses of a transgenic mouse that expresses an octanal receptor in almost all olfactory sensory neurons.